Multiple system atrophy (MSA) is a progressive, neurodegenerative disorder characterized clinically by the combination of varying degrees of Parkinsonism and/or cerebellar ataxia, autonomic dysfunction and an inexorable progression to death in a few years, whereas Parkinson's disease (PD) and PD with autonomic failure (PD_AF) have a more benign prognosis. This project is part of a highly integrated PPG focused on defining the diagnosis, course and pathogenesis of MSA. This project is based on the central hypothesis that clinical and laboratory indices, especially autonomic indices, will differentiate MSA, PD, and PD_AF and will predict outcome. We will prospectively test the hypothesis within three specific aims. Specific aim #1 will differentiate MSA from PD and PD_AF using selected clinical features, a standardized autonomic symptom profile evaluating seven domains of autonomic dysfunction, and standardized autonomic function tests. These evaluate cardiovagal, adrenergic, and sudomotor functions. Specific aim #2 will be achieved in a series of mechanistic studies undertaken to identify pathophysiologic autonomic differences between MSA, PD, and PDAF. These studies will be focused on autonomic regulation at the levels of autonomic neurons, arteriole, and vein. The autonomic lesion in MSA is preganglionic, that of PD postganglionic (at least in the heart), while that of PD_AF is uncertain (but likely to be postganglionic sympathetic). Within this specific aim, we will undertake direct microneurographic recordings of sympathetic discharges of the peroneal nerve to differentiate the three conditions. We will undertake pharmacologic dissection studies to differentiate preganglionic from postganglionic disorders. We will also be able to undertake direct studies on vasoreactivity of veins in vivo to provide the same information in a different effector (vein instead of arteriole). Specific aim #3 is a prospective study of patients with MSA, PD, and PD_AF where we evaluate predictors of more rapid rate of progression. Specifically, we predict that certain indices (autonomic and clinical) predict outcome, defined as the time in months from (a) first clinical feature and (b) diagnosis, to Hoehn and Yahr stage IV. Specifically, we posit that a higher deficit score on autonomic reflex screen, on the symptom profile, and certain clinical features (dopa unresponsiveness, absence of dyskinesias) are predictive of a bad outcome. As part of a PPG, these patients will also be evaluated in Project 1 (for risk factors) via the Data and Administrative and Clinical Cores, DNA from these patients will, via the DNA core, be provided to Projects 2 and 3 for molecular studies on synuclein and patients will be earmarked for eventual pathologic confirmation and segregation into the appropriate diagnostic groups.